Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/35—Allergens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
  • A61K2039/515—Animal cells
  • A61K2039/5156—Animal cells expressing foreign proteins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
  • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
  • A61K2039/523—Bacterial cells; Fungal cells; Protozoal cells expressing foreign proteins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
  • A61K2039/525—Virus
  • A61K2039/5256—Virus expressing foreign proteins

Definitions

• Allergic reactions result when an individual's immune system overreacts, or reacts inappropriately, to an encountered antigen.
• the antigen is taken up by antigen presenting cells (APC; e.g., macrophages and dendritic cells) that degrade the antigen and then display antigen fragments to T cells.
• APC antigen presenting cells
• T cells in particular CD4 + "helper" T-cells, respond by secreting a collection of cytokines that have effects on other immune system cells. The profile of cytokines secreted by responding CD4 + T cells determines whether subsequent exposures to the antigen will induce allergic reactions.
• Two classes of CD4 T cells (Thl and Th2) influence the type of immune response that is mounted against an antigen.
• bacteria or yeast are used as microorganisms to express and deliver allergenic proteins to individuals to treat or prevent allergic responses, including anaphylactic allergic responses, to the allergens.
• Gram-positive and gram-negative bacteria may be used in the present invention has delivery vehicles.
• Antigens expressed by the bacteria may be secreted or non- secreted.
• Secretion of proteins may involve secretion into the cellular medium.
• secretion may involve secretion into the periplasm.
• Secretion of polypeptides may be facilitated by secretion signal peptides.
• microorganisms expressing allergenic compounds may be administered to subjects in compositions as attenuated microorganisms, non- pathogenic microorganisms, non-infectious microorganisms, or as killed microorganisms.
• the killed microorganisms are killed without degrading the anti genie properties of the polypeptides.
• inducible promoter means a promoter site which is activated directly by the presence or absence of a chemical agent or indirectly by an environmental stimulus such as temperature changes.
• a promoter is the region of DNA at which the enzyme RNA polymerase binds and initiates the process of gene transcription.
• a person is susceptible to an allergic reaction if (i) that person has ever displayed symptoms of allergy after exposure to a given antigen; (ii) members of that person's genetic family have displayed symptoms of allergy against the allergen, particularly if the allergy is known to have a genetic component; and/or (iii) antigen-specific IgE are found in the individual, whether in serum or on mast cells.
• Gram-positive bacteria have also been studied as delivery vehicles for proteins to modulate an immune response in a subject.
• WO 97/14806 describes the use of Lactococcus to deliver polypeptides into a body to enhance the immune response to the polypeptides.
• WO 97/14806 does not teach the use of Lactococcus to treat patients with food allergies and venom allergies which may result in anaphylaxis
• yeast are used as protein delivery microorganisms. It is well known that yeast are amenable to genetic manipulation to express a protein or proteins of choice (Ausubel et al. supra). Furthermore, in general most yeast are non-pathogenic.
• the inventive expression of allergens by microorganisms is regulated so that synthesis occurs at a controlled time after the live microorganism is administered to an individual.
• the induction of protein synthesis is regulated so that activation occurs after the microorganism(s) is taken up by antigen-presenting cells (APCs) and phagocytosed into the endosome.
• a desirable result of this regulation is that production of the allergen of interest occurs inside the APCs and therefore reduces or eliminates the exposure of the allergen to IgE molecules bound to the surface of histamine-releasing mast cells and basophils. This reduces or eliminates the risk of anaphylaxis during administration of microorganisms that produce anaphylactic antigens.
• any allergen may be produced by microorganisms in accordance with the present invention.
• Preferred allergens are found in certain foods, venom, drugs or rubber and are capable of eliciting allergic responses, and in particular anaphylactic allergic responses in an individual.
• Particularly preferred allergens are protein or polypeptide allergens.
• microorganisms of the present invention produce allergenic proteins that elicit allergies, possibly anaphylaxis, and are found in foods, venoms, drugs, and rubber-based products.
• Particularly preferred allergenic proteins that induce anaphylaxis such as several protein allergens found in food (peanut, milk, egg, wheat), insect venom (i.e. bees, reptiles), drugs, and latex.
• a single compound e.g., a single protein
• the invention can be applied to more complex allergens. Therefore, collections of more than one antigen can be used so that immune responses to multiple antigens may be modulated simultaneously.
• Appendix A presents a representative list of certain known protein antigens. As indicated, the amino acid sequence is known for many or all of these proteins, either through knowledge of the sequence of their cognate genes or through direct knowledge of protein sequence, or both. Of particular interest are anaphylactic antigens.
• Cytokines that, when expressed during antigen delivery into cells, induce a Thl response in T cells include IL-12, IL-2, 1-18, IL-1 or fragments thereof, IFN , and/or IFN ⁇ .
• Other compounds that are immunomodulatory include immunological inducing agents. These inducing agents prompt the expression of Thl stimulating cytokines by T-cells and include factors such as, CD40, CD40 ligand, oligonucleotides containing CpG motifs, TNF, and microbial extracts such as preparations of Staphylococcus aureus, heat killed Listeria, and modified cholera toxin, etc.
• immunologic adjuvant include gel-type adjuvants (e.g. aluminum hydroxide/aluminum phosphate, calcium phosphate), microbial adjuvants (e.g. DNA such as CpG motifs; endotoxin such as monophosphoryl lipid A; exotoxins such as cholera toxin, E. coli heat labile toxin, and pertussis toxin; and muramyl dipeptide), oil-emulsion and emulsifier-based adjuvants (e.g.
• gel-type adjuvants e.g. aluminum hydroxide/aluminum phosphate, calcium phosphate
• microbial adjuvants e.g. DNA such as CpG motifs; endotoxin such as monophosphoryl lipid A; exotoxins such as cholera toxin, E. coli heat labile toxin, and pertussis toxin; and muramyl dipeptide
• particulate adjuvants e.g. liposomes, biodegradable microspheres, and saponins
• synthetic adjuvants e.g. nonionic block copolymers, muramyl peptide analogues, polyphosphazene, and synthetic polynucleotides.
• LPS monophosphoryl lipid A
• MPLA monophosphoryl lipid A
• Some polymers are also adjuvants.
• polyphosphazenes are described in U.S. Patent No. 5,500,161 to Andriavnov, et al. These can be used not only to encapsulate the microorganisms but also to enhance the immune response to the antigen.
• compositions of the present invention may be formulated for delivery by any route.
• the compositions are formulated for injection, ingestion, or inhalation. Modifications and variations of the methods and compositions described herein are intended to be within the scope of the following claims.
• mice injected with allergen-producing bacteria Blood was collected from the tail vein of each mouse used before the first injection. Enough blood was collected for antibody ELISA for each allergen and E. coli proteins. On Day Zero each mouse was injected with 100 microliters of the killed E. coli samples subcutaneously in the left hind flank. The mice were injected for the second time on Day 14 using the same procedure as Day Zero. On Day 21, a second blood sample was collected from each mouse. Blood samples at Day 0 and Day 21 were assayed for IgGl and IgG2a antibodies to either Ara h 1, Ara h 2, or Ara h 3 by an ELISA assay.
• mice injected with E. coli producing Ara h 1 did not give detectable levels of any immunoglobulin to the Ara h 1 allergen and therefore, that data are not shown. Without limitation to theory, we speculate that this may be due to the relatively small amounts of Ara h 1 produced by these cells (see previous discussion).
• Mice injected with E. coli producing Ara h 2 contained relatively high levels of IgGl and IgG2a. Again, without limitation to the cause, we speculated that this may be due to the amount of Ara h 2 released from these cells (see discussion above).
• Mice injected with E. coli producing Ara h 3 contained relatively high levels of IgG2a (indicative of a Thl -type response) and elicited relatively low levels of IgGl (indicative of a Th2- type response.
• Latex B-serum -1,3-glucanase (Hev b 2) and a component of the microhehx (Hev b 4) are major Latex allergens J nat Rubb Res 10 82-99

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• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Medicinal Chemistry (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Peptides Or Proteins (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Micro-Organisms Or Cultivation Processes Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 2000
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